ABSTRACT Ever since the first report from Australia in 1948, followed by many publications from Uganda and Congo, the only treatment for the emerging infectious disease now known as Buruli ulcer, caused by Mycobacterium ulcerans and affecting mainly children in swampy areas of tropical countries, was prolonged surgery, i.e., excision and skin grafting. In the past few years, our laboratory revived the mouse footpad model of M. ulcerans disease and demonstrated that treatment for two months with amikacin (or streptomycin) and rifampin, used in the mouse at doses equipotent to human doses, was highly active (bactericidal). Clinical trials have since demonstrated that, when administered to humans, the same drug combination is also very active. Surgery was avoided in almost half of the cases and facilitated in the remaining cases. Because of the practical inconvenience, the risk of toxicity and accidental viral transmission through daily injections of aminoglycoside, our main objective is to develop a totally oral drug regimen of Buruli ulcer and to search for an active preventive treatment. To address these issues, our first aim is to create a M. ulcerans containing luxAB reporter gene in order to overcome the difficulties related to the slow growth of M. ulcerans in vivo (division time 3-5 days),and its relatively poor and lengthy growth in vitro. Our second aim is to test the ability of the new recombinant M. ulcerans to produce toxin (because of the relative instabilty of mycolactone-encoding genes in the plasmid ) and virulence for the mouse, and its validity for rapid in vitro and in vivo assessment of drug susceptibility in comparison with standard models. Because all drugs tested to date, with the exception of aminoglycosides and rifampin, have only bacteriostatic activity against M. ulcerans, our third aim is to systematically screen for novel in vitro and in vivo active drugs and drug combinations using the new lux-containing M. ulcerans. Applying the standard rule in public health prevention is better than cure, our fourth aim is to test the validity of the recombinant M. ulcerans for vaccine assessment and compare the efficacy of BCG, DNA vaccines and newly proposed vaccines in the prevention of M. ulcerans disease. The main experimental model we propose to use is the mouse footpad model of experimental chemotherapy of M. ulcerans disease because the results obtained with this model have proved to be predictive of results in humans.